title: Accelerated recovery of renal mitochondrial and tubule homeostasis with SIRT1/PGC-1α activation following ischemia-reperfusion injury.
abstract: Kidney ischemia-reperfusion (I/R) injury elicits cellular injury in the proximal tubule, and mitochondrial dysfunction is a pathological consequence of I/R. Promoting mitochondrial biogenesis (MB) as a repair mechanism after injury may offer a unique strategy to restore both mitochondrial and organ function. Rats subjected to bilateral renal pedicle ligation for 22 min were treated once daily with the SIRT1 activator SRT1720 (5mg/kg) starting 24h after reperfusion until 72h-144 h. SIRT1 expression was elevated in the renal cortex of rats after I/R+vehicle treatment (IRV), but was associated with less nuclear localization. SIRT1 expression was even further augmented and nuclear localization was restored in the kidneys of rats after I/R+SRT1720 treatment (IRS). PGC-1α was elevated at 72 h-144 h in IRV and IRS kidneys; however, SRT1720 treatment induced deacetylation of PGC-1α, a marker of activation. Mitochondrial proteins ATP synthase β, COX I, and NDUFB8, as well as mitochondrial respiration, were diminished 24h-144 h in IRV rats, but were partially or fully restored in IRS rats. Urinary kidney injury molecule-1 (KIM-1) was persistently elevated in both IRV and IRS rats; however, KIM-1 tissue expression was attenuated in IRS rats. Additionally, sustained loss of Na(+),K(+)-ATPase expression and basolateral localization and elevated vimentin in IRV rats was normalized in IRS rats, suggesting restoration of a differentiated, polarized tubule epithelium. The results suggest that SRT1720 treatment expedited recovery of mitochondrial protein expression and function by enhancing MB, which was associated with faster proximal tubule repair. Targeting MB may offer unique therapeutic strategy following ischemic injury.
authors.affiliation: Center for Cell Death, Injury, and Regeneration, Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA. Electronic address: funkj@musc.edu.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Funk
authors.forename: Rick G
authors.initials: RG
authors.lastname: Schnellmann
mesh_terms: D000818:Animals; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology / Q000627:therapeutic use; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D056564:Sirtuin 1 / Q000096:biosynthesis*; D014157:Transcription Factors / Q000096:biosynthesis*
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; C525422:SRT1720; D014157:Transcription Factors; C488368:Sirt1 protein, rat; D056564:Sirtuin 1
keywords: ATP synthase subunit β; ATPβ; Acute kidney injury; COX I; Drp1; Ischemia–reperfusion; KIM-1; Mfn2; Mitochondrial biogenesis; Mitochondrial dysfunction; NADH dehydrogenase (ubiquinone) 1 beta subcomplex 8; NDUFB8; PGC-1α; Proximal tubule; SIRT1; SRT1720; cytochrome c oxidase subunit I; dynamin related protein 1; kidney injury molecule 1; mitofusin-2; peroxisome proliferator activated receptor γ coactivator-1α; sCr; serum creatinine; sirtuin 1